Transcriptional coactivator MED15 is required to maintain β-cell maturity

The Mediator complex, a vital transcriptional coregulator in eukaryotes, partners with transcription factors to orchestrate gene transcription and in turn many developmental and physiological processes. Mediator subunit MED15 is required for the pre-natal development and post-natal maturation of pancreatic β-cells in mice. However, whether MED15 plays a role in β-cell function after initial development and throughout adulthood is unknown. To investigate the role of MED15 in β-cells post-maturation, we induced a β-cell specific Med15 knockout at six weeks age in male and female mice. This post-developmental Med15 ablation led to glucose intolerance and impaired insulin secretion. RNA-sequencing revealed downregulation of β-cell maturation markers, indicating that MED15 is continuously required to maintain β-cell functionality. Further, we implanted insulin pellets into Med15 knockout mice to lower blood glucose and used RNA-seq to validate that the transcriptional changes we observed are a direct consequence of Med15 loss and not an indirect effect of hyperglycemia arising in the knockout mice. In sum, our study shows that MED15 is continuously required after weaning to maintain functional β-cell maturity.